Certain cycloalkyl imidazopyrimidines; a new class of gaba brainreceptor ligands

ABSTRACT

This invention encompasses compounds of the formula:  &lt;IMAGE&gt;  and pharmaceutically acceptable non-toxic salts thereof wherein n is 0,1 or 2 and X is -N=C-R9 or NR10 -C=T where R1, R2, R3, and R9 and R10 and X, Y, W and T are variables. These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdoes with benzodiazepine type drugs, and enhancement of alertness.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain cycloalkyl imidazopyrimidines whichselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness. The interaction of 2-aryl substitutedimidazo-quinazolines of the invention with a GABA binding site, thebenzodiazepines (BDZ) receptor, is described. This interaction resultsin the pharmacological activities of these compounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 30 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. In most regions of the brain, GABA isassociated with local inhibitory neurons and only in two regions is GABAassociated with longer projections. GABA mediates many of its actionsthrough a complex of proteins localized both on cell bodies and nerveendings; these are called GABAa receptors. Postsynaptic responses toGABA are mediated through alterations in chloride conductance thatgenerally, although not invariably, lead to hyperpolarization of thecell. Recent investigations have indicated that the complex of proteinsassociated with postsynaptic GABA responses is a major site of actionfor a number of structurally unrelated compounds capable of modifyingpostsynaptic responses to GABA. Depending on the mode of interaction,these compounds are capable of producing a spectrum of activities(either sedative, anxiolytic, and anticonvulsant, or wakefulness,seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281.).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 μM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. The data were interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor agonist (+) bicuculline; the stereoisomer(-) bicuculline is much less active (Tallman et al., 1978, Nature, 274:383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity of negativecooperativity. In these studies, Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have molecular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Sieghart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine, (Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous. A biochemical test forthe pharmacological and behavioral properties of compounds that interactwith the benzodiazepine receptor continues to emphasize the interactionwith the GABAergic system. In contrast to the benzodiazepines, whichshow an increase in their affinity due to GABA (Tallman et al., 1978,Nature 274: 383-85, Tallman et al., 1980, Science 207: 274-81),compounds with antagonist properties show little GABA shift (i.e.,change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature294: 763-65), and the inverse agonists actually show a decrease inaffinity due to GABA [(Braestrup & Nielson 1981, Nature 294: 472-474)].Thus, the GABA shift predicts generally the expected behavioralproperties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For example, U.S. Pat. Nos. 4,713,383, and 4,643,999 andEur. Patent Applications Nos. 181,282, 219,748 and 263,071 teach variousbenzodiazpine agonists and antagonists useful in the treatment ofanxiety. U.S. Pat. No. 4,643,999 discloses compounds of the formula:##STR2## wherein R is an aryl of 6 to 12 carbon atoms, R₁ is selectedfrom the group consisting of hydrogen and alkyl, alkoxy and alkylthio of1 to 5 carbon atoms when R₂ and R₃ together form a carbon-nitrogen bondor R₁ and R₂ together are=0 when R₃ is selected from the groupconsisting of hydrogen, alkyl of 1 to 5 carbon atoms and alkenyl of 2 to5 carbon atoms, R₄ is selected from the group consisting of alkoxy andalkylthio of 1 to 5 carbon atoms, R₅ is selected from the groupconsisting of hydrogen and alkyl of 1 to 5 carbon atoms, and theirnon-toxic, pharmaceutically acceptable acid addition salts.

U.S. Pat. No. 4,713,383 teaches compounds of the formula: ##STR3##wherein R₁ =(un)substituted Ph, (dihydro)furanyl, tetrahydrofuranyl,(dihydro)thienyl, tetrahydrothienyl, pyranyl, ribofuranosyl, allC-attached;

R₂ =H, alkyl; X=O, S, R₃ N; R₃ =H, alkenyl, alkynyl, C₃₋₂₀ cycloalkyl,(un)substituted alkyl, aryl, aralkyl, where aryl is Ph, pyridinyl,thienyl, furanyl; ring A may be substituted by alkyl, alkoxy, halo,amino, alkylthio, etc.

European Patent Application EP 181,282 discloses compounds of theformula: ##STR4## wherein R₁ =(substituted) Ph or heterocycle;

R₂ =H, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl, aryl; R₃ =H,alkyl, alkoxy, HO, halo, F₃ C, O₃ N, H₂ N, alkylthio, alkylsulfinyl,alkylsulfonyl, aralkoxy; X=O, S, NR₄ ;

R₄ =H, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, aryl, (substituted)aminoaklyl, hydroxyalkyl.

European Patent Application EP 217,748 teaches compounds of the formula:##STR5## are wherein A=atoms to complete a fused, (un)substituted,(un)saturated, carbocyclic or heterocyclic ring comprising C, O, N, andS; X=O, S, RN; R=H, OH, hydroxyalkyl, aryl, H₂ NC(:NH), alkyl, alkenyl,alkynyl, optionally with hetero atom interrupters; R=(un)substitutedcarbocyclyl, heterocyclyl; R₂ =(un)substituted Ph.

European Patent Application EP 263,071 discloses compounds of theformula ##STR6## wherein X=O, NR, S:

R=H, lower alkyl, alkenyl, alkynyl;

R₁ =(substituted) Ph, furyl, thienyl, pyridyl, pyrrolyl, etc;

ring A=C₅₋₈ cycloalkene, heterocycle, etc., each ring A beingunsubstituted or substituted by lower alkyl, alkoxy, OH, halogen, CF₃,NO₂, carbamoyl, carbamoylalkyl, etc.

These compounds differ from the compounds of the present invention. U.S.Pat. No. 4,713,383, and European Patent Applications Nos. 181,282,217,748 and 263,071 each teach carbocyclic compounds having anadditional nitrogen atom in the carbocyclic system. U.S. Pat. No.4,643,999 teaches imidazopyrimidines lacking the aryl substituents atposition 2, the nitrogen in the ring system at position 9, and othervarious ring substituents of the compounds of the present invention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingalertness, treatment of seizure, anxiety, and sleep disorders, andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I: ##STR7## andpharmaceutically acceptable non-toxic salts thereof wherein: n is 0, 1or 2;

R₁, R₂, and R₃ are hydrogen or straight chain or branched lower alkylhaving 1-6 carbon atoms;

W is phenyl, thienyl, or pyridyl, unsubstituted or mono or disubstitutedwith halogen, lower alkyl, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms;

Y is --R₄, --OR₄, --COR₄, --CO2R₄, --OCOR₄, --CONR₄ R₅, --(CH₂)_(n) NR₄R₅ where n is 0, 1 or 2 and R₄ and R₅ are the same or different andrepresent hydrogen, aryl or heteroaryl, straight or branched chain loweralkyl having 1-6 carbon atoms, aryl or heteroaryl straight or branchedchain lower alkyl having 1-6 carbon atoms, and NR₄,R₅ may also representN-alkyl piperazinyl,morpholinyl, piperidinyl or pyrrolidinyl, or NR₄ CO₂R₆ where R₄ is hydrogen, aryl or heteroaryl, straight or branched chainlower alkyl having 1-6 carbon atoms, aryl or heteroaryl straight orbranched chain lower alkyl having 1-6 carbon atoms and R₆ is straight orbranched chain lower alkyl having 1 to 6 carbon atoms or aryl, or--C(OH)R₇ R₈ where R₇ and R₈ are the same or different and representhydrogen, branched or straight chain lower alkyl having 1-6 carbonatoms, aryl or aryl straight or branched chain lower alkyl having 1-6carbon atoms; and

X is ##STR8## with the proviso that when X is ##STR9## T is oxygen orsulfur and R₁₀ is hydrogen, straight or branched chain lower alkylcontaining 1-6 carbon atoms or COR₁₁ where R₁₁ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, amino, alkylamino or dialkylamino where each alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, and when X is ##STR10## R₉ is hydrogen,halogen, cyano, aryloxy, straight or branched chain lower alkoxy having1-6 carbon atoms, amino, arylamino, alkylamino, dialkylamino orarylalkylamino where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms, OCOR₁₁ where R₁₁ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, amino, alkylamino, dialkylamino, arylamino, or arylalkylamino where each alkyl is a straight orbranched chain lower alkyl having 1-6 carbon atoms, or CONHR₁₂ where R₁₂is hydrogen or branched or straight chain lower alkyl having 1-6 carbonatoms.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs thereof and are useful inthe diagnosis and treatment of anxiety, sleep, and seizure disorders,overdose with benzodiazepine drugs, and enhancement of memory.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1L show representative 2-aryl substitutedimidazo[1,2-c]quinazolines of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula: ##STR11## andpharmaceutically acceptable non-toxic salts thereof wherein: n is 0, 1or 2;

R₁, R₂, and R₃ are hydrogen or straight chain or branched lower alkylhaving 1-6 carbon atoms;

W is phenyl, thienyl, or pyridyl, unsubstituted or mono or disubstitutedwith halogen, lower alkyl, or straight or branched chain lower alkoxyhaving 1-6 carbon atoms;

Y is --R₄, --OR₄, --COR₄, --CO2R₄, --OCOR₄, --CONR₄ R₅, --(CH₂)_(n) NR₄R₅ where n is 0, 1 or 2 and R₄ and R₅ are the same or different andrepresent hydrogen, aryl or heteroaryl, straight or branched chain loweralkyl having 1-6 carbon atoms, aryl or heteroaryl straight or branchedchain lower alkyl having 1-6 carbon atoms, and NR₄,R₅ may also representN-alkyl piperazinyl,morpholinyl, piperidinyl or pyrrolidinyl, or NR₄ CO₂R₆ where R₄ is hydrogen, aryl or heteroaryl, straight or branched chainlower alkyl having 1-6 carbon atoms, aryl or heteroaryl straight orbranched chain lower alkyl having 1-6 carbon atoms and R₆ is straight orbranched chain lower alkyl having 1 to 6 carbon atoms or aryl, or--C(OH)R₇ R₈ where R₇ and R₈ are the same or different and representhydrogen, branched or straight chain lower alkyl having 1-6 carbonatoms, aryl or aryl straight or branched chain lower alkyl having 1-6carbon atoms; and

X is ##STR12## with the proviso that when X is ##STR13## T is oxygen orsulfur and R₁₀ is hydrogen, straight or branched chain lower alkylcontaining 1-6 carbon atoms or COR₁₁ where R₁₁ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, amino, alkylamino or dialkylamino where each alkyl is a straight or branched chain lower alkylhaving 1-6 carbon atoms, and when X is ##STR14## R₉ is hydrogen,halogen, cyano, aryloxy, straight or branched chain lower alkoxy having1-6 carbon atoms, amino, arylamino, alkylamino, dialkylamino orarylalkylamino where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms, OCOR₁₁ where R₁₁ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, amino, alkylamino, dialkylamino, arylamino, or arylalkylamino where each alkyl is a straight orbranched chain lower alkyl having 1-6 carbon atoms, or CONHR₁₂ where R₁₂is hydrogen or branched or straight chain lower alkyl having 1-6 carbonatoms.

The invention also encompasses compounds of formula II: ##STR15## andthe pharmaceutically acceptable non-toxic salts thereof wherein Y ishydrogen, lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6carbon atoms, phenyl alkyl having 1-3 carbon atoms, carboalkoxy having1-6 carbon atoms, --(CH₂)_(n) NR₄ R₅ or --CONR₄ R₅ with n is 0 or 1 andR₄ and R₅ are the same or different and represent hydrogen, aryl orheteroaryl, straight or branched chain lower alkyl having 1-3 carbonatoms, aryl or heteroaryl straight or branched chain lower alkyl having1-3 carbon atoms, and NR₄,R₅ may also represent N-alkyl piperazinyl,morpholinyl, piperidinyl or pyrrolidinyl, or NR₄ CO₂ R₆ where R₄ ishydrogen or methyl and R₆ is straight or branched chain lower alkylhaving 1 to 6 carbon atoms or aryl, or --C(OH)R₇ R₈ where R₇ and R₈ arethe same or different and represent hydrogen, branched or straight chainlower alkyl having 1-6 carbon atoms, aryl or aryl straight or branchedchain lower alkyl having 1-6 carbon atoms;

W is phenyl, unsubstituted or mono or disubstituted with halogen, loweralkyl, or straight or branched chain lower alkoxy having 1-6 carbonatoms; and

R₉ is hydrogen, halogen, aryloxy, alkoxy having 1-6 carbon atoms orOCOR₁₁ where R₁₁ is hydrogen, straight or branched chain lower alkylhaving 1-6 carbon atoms, alkoxy having 1-6 carbon atoms, amino ordialkyl amino having 1-6 carbon atoms.

The invention additionally encompasses compounds of formula III:##STR16## and the pharmaceutically acceptable non-toxic salts thereofwherein Y is hydrogen, lower alkyl having 1-6 carbon atoms, alkanoylhaving 1-6 carbon atoms, phenyl alkyl having 1-3 carbon atoms,carboalkoxy having 1-6 carbon atoms, --(CH₂)_(n) NR₄ R₅ with n is 0 or 1and R₄ and R₅ are the same or different and represent hydrogen, aryl orheteroaryl, straight or branched chain lower alkyl having 1-3 carbonatoms, aryl or heteroaryl straight or branched chain lower alkyl having1-3 carbon atoms, and NR₄,R₅ may also represent N-alkyl piperazinyl,morpholinyl, piperidinyl or pyrrolidinyl, or NR₄ CO₂ R₆ where R₄ ishydrogen or methyl and R₆ is straight or branched chain lower alkylhaving 1 to 6 carbon atoms or aryl, or --C(OH)R₇ R₈ where R₇ and R₈ arethe same or different and represent hydrogen, branched or straight chainlower alkyl having 1-6 carbon atoms, aryl or aryl straight or branchedchain lower alkyl having 1-6 carbon atoms;

W is phenyl, unsubstituted or mono or disubstituted with halogen, loweralkyl, or straight or branched chain lower alkoxy having 1-6 carbonatoms; and

T is oxygen or sulfur.

Furthermore, the invention encompasses compounds of formula IV:##STR17## and the pharmaceutically acceptable non-toxic salts thereofwherein Y is hydrogen, lower alkyl having 1-6 carbon atoms, alkanoylhaving 1-6 carbon atoms, phenyl alkyl having 1-3 carbon atoms,carboalkoxy having 1-6 carbon atoms, --(CH₂)_(n) NR₄ R₅ or --CONR₄ R₅with n is 0 or 1 and R₄ and R₅ are the same or different and representhydrogen, aryl or heteroaryl, straight or branched chain lower alkylhaving 1-3 carbon atoms, aryl or heteroaryl straight or branched chainlower alkyl having 1-3 carbon atoms, and NR₄,R₅ may also representN-alkyl piperazinyl, morpholinyl, piperidinyl or pyrrolidinyl, or NR₄CO₂ R₆ where R₄ is hydrogen or methyl and R₆ is straight or branchedchain lower alkyl having 1 to 6 carbon atoms or aryl, or --C(OH)R₇ R₈where R₇ and R₈ are the same or different and represent hydrogen,branched or straight chain lower alkyl having 1-6 carbon atoms, aryl oraryl straight or branched chain lower alkyl having 1-6 carbon atoms; and

W is phenyl, unsubstituted or mono or disubstituted with halogen, loweralkyl, or straight or branched chain lower alkoxy having 1-6 carbonatoms.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. Iand their pharmaceutically acceptable salts.

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3:433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20'. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at -20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05M Tris CHlbuffer (pH 7.4 at 40° C.).

Incubations contain 100 μl of tissue homogenate, 100 μl of radioligand0.5 nM (³ H-RO15-1788 specific activity 80 Ci/mmol), drug or blocker andbuffer to a total volume of 500 μl. Incubations are carried for 30 minat 4° C. then are rapidly filtered through GFB filters to separate freeand bound ligand. Filters are washed twice with fresh 0.05M Tris HClbuffer (pH 7.4 at 4° C.) and counted in a liquid scintillation counter.1.0 μM diazepam is added to some tubes to determine nonspecific binding.Data are collected in triplicate determinations, averaged and %inhibition of total specific binding is calculated. Total SpecificBinding=Total-Nonspecific. In some cases, the amounts of unlabeled drugsis varied and total displacement curves of binding are carried out. Dataare converted to a form for the calculation of IC₅₀ and Hill Coefficient(nH).

Data for the compounds of this invention are listed in Table I.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                          IC.sub.50 (μM)                                            ______________________________________                                         1               0.007                                                         5               0.007                                                        12               0.400                                                        13               0.800                                                        14               0.010                                                        18               0.010                                                        21               0.003                                                        24               0.030                                                        25               0.003                                                        28               0.150                                                        31               2.0                                                          33               0.100                                                        39               5.0                                                          ______________________________________                                         .sup.1 Compound numbers relate to compounds shown in FIG. 1.             

Compounds 1, 5, 21, and 25 are particularly preferred embodiments of thepresent invention because of their potency in binding to the GABAareceptor.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Scheme I. Those having skill in the art will recognize thatthe starting materials may be varied and additional steps employed toproduce compounds encompased by the present invention, as demonstratedby the following examples. ##STR18##

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE I ##STR19##

A mixture of Ethyl-4,4-dicarboethoxycyclohexanone-2-carboxylate (100 g)and guanidine carbonate (18.9 g) and dry ethanol (200 mL) was refluxedfor 2.5 h. The mixture was cooled and 300 mL water and 20 mL acetic acidwere added. The precipitate that formed was collected and air dried toyield 2-Amino-6,6-dicarboethoxy-5,6,7,8-tetrahydro-4(3H)-quinazolinone.

EXAMPLE II ##STR20##

To a solution of2-Amino-6,6-dicarboethoxy-5,6,7,8-tetrahydro-4(3H)-quinazolinone (75 g)in acetic acid (250 mL) at reflux was added a solution of sodium nitrite(75 g) in water (100 mL) in a dropwise fashion over a period of 45 min.The solution was cooled and the solvent removed in vacuo. The subsequentaddition of 300 mL of water precipitated a solid which was collected anddried to yield6,6-Dicarboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione.

EXAMPLE III ##STR21##

A solution of6,6-Dicarboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione (25 g)in 1N NaOH (350 mL) was stirred at 40° C. for 35 min. The solution wascooled in an ice bath and acidified with 35 mL of concentrated HCl. Theprecipitate that formed was collected and refluxed in 20 ml ofdimethylformamide (DMF) for 2 h. The reaction was cooled and the DMFremoved in vacuo. To the resulting mixture 40 mL of water was added andthe solid collected and dried to yield6-Carboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione.

EXAMPLE IV ##STR22##

A mixture of6-Carboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione (7.12 g)and POCl₃ (100 mL) was refluxed overnight. The mixture was cooled andthe excess POCl₃ removed in vacuo. After the mixture was further cooledto 0° C., 20 mL of dry ethanol was added and the resulting mixtureneutralized to pH 7 with 10% aqueous ammonium hydroxide. The solid whichprecipitated was collected and dried to yield6-Carboethoxy-2,4-dichloro-5,6,7,8-tetrahydroquinazoline.

EXAMPLE V ##STR23##

A mixture of 6-Carboethoxy-2,4-dichloro-5,6,7,8-tetrahydroquinazoline(7.68 g), 2-propanol (7 mL) and 30% ammonium hydroxide (12 mL) washeated in a sealed tube at 130° C. for 20 min. The tube was cooled and20 mL of H₂ O was added to the mixture. The solid which precipitated wascollected and dried to yield4-Amino-6-carboethoxy-2-chloro-5,6,7,8-tetrahydroquinazoline.

EXAMPLE VI ##STR24##

A mixture of4-Amino-6-carboethoxy-2-chloro-5,6,7,8-tetrahydroquinazoline (6.4 g) andconcentrated HCl (10 mL) was refluxed for 20 min. After the solvent wasremoved in vacuo, 250 ml ethanol saturated with HCl was added, and themixture was further refluxed for 1 hour. The solvent was subsequentlyremoved in vacuo and 15 ml of water was added to the mixture. Thesolution was then brought to pH 4 with 30% ammonium hydroxide and thesolid subsequently collected and dried to yield4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone.

EXAMPLE VII ##STR25##

A solution of4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone (262 mg)and 2'-fluoro-bromoacetophenone (217 mg) in dry DMF (10 mL) was refluxedunder nitrogen for 1.5 h. The solution was cooled and 40 mL water isadded. The precipitate was collected and washed successively with 10 mLof methanol and 20 mL hot ethyl acetate to yield9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 1) melting at 257°-277° C.

EXAMPLE VIII

The following compounds were prepared essentially according to theprocedures described in Examples I-VII:

(a)2-(4-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 2), m.p. 305°-307° C.

(b)2-(2-Methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 3). m.p. 283°-285° C.

(c)2-(2-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 4). m.p. 281°-283° C.

(d)2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 5). m.p. 314°-315° C.

(e)2-(4-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 6). m.p. 301°-303° C.

(f)2-3-(Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 7). m.p. 302°-303° C.

(g) 2-Phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 8). m.p. 314°-315° C.

(h)2-(3-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 9). m.p. 295°-296° C.

(i)9-Carboethoxy-2-(3-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 10). m.p. 227°-228° C.

(j)2-(4-Methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 11).

(k)2-Phenyl-8,9-dihydro-7H-cyclopent[g]-imidazo[1,2-c]-pyrimidin-5(6H)-one(Compound 12). m.p. 281°-282° C.

(l)2-Phenyl-8,9,10,11-tetrahydro-7H-cyclohept[g]-imidazo[1,2-c]pyrimidin-5(6H)-one(Compound 13) m.p. 283°-285° C.

EXAMPLE IX ##STR26##

To 10 mL of 2-propanol saturated with HCl gas was added9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(100 mg) and the mixture was heated in a sealed tube at 150° C. for 1hour. The reaction was cooled and the solvent was evaporated in vacuo.To the reaction mixture was added 10 mL of H₂ O and the mixture was thenbrought to pH 7 with ammonium hydroxide. The solid was collected anddried to yield9-Carboisopropoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]quinazolin-5(6H)-one(Compound 14). m.p. 282°-285° C.

EXAMPLE X

The following compounds were prepared essentially according to theprocedure of Example IX:

(a)9-Carboisopropoxy-2-(3-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 15). m.p. 270°-272° C.

(b)9-Carbobutoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 16). m.p. 218°-220° C.

EXAMPLE XI ##STR27##

To 20 mL of 1N NaOH was added9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(400 mg). After the solid dissolved, the mixture was stirred for 40minutes at 60° C., cooled and the pH adjusted to 3 with concentratedHCl. The solid was collected and dried to yield9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 17). m.p.>325° C.

EXAMPLE XII ##STR28##

A mixture containing9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(150 mg) and 1,1-carbonyldiimadazole (120 mg) in DMF (5 mL) was heatedto 60° C. for 15 minutes after which time the reaction was cooled and 2mL of dimethylamine added. The reaction was allowed to stand at roomtemperature for 1 hour. To the mixture was then added 10 mL of H₂ O andthe resultant product was collected and dried to yield9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 18) m.p.>325° C.

EXAMPLE XIII

The following compounds were prepared essentially according to theprocedure of Example XII:

(a)9-(N-Methylpiperazinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 19) m.p. 312°-314° C.

(b)9-(N-Benzylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 20) m.p. 305°-306° C.

(c)9-(Piperidinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 21).

(d)9-(Pyrrolidinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 22).

(e)9-(Morpholinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 23).

EXAMPLE XIV ##STR29##

To 100 mL of anhydrous tetrahydrofuron was added9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(70 mg). The mixture was refluxed until the solid had completelydissolved. Refluxing was ceased and 100 mg of lithium aluminum hydridewas added to the solution. This mixture was allowed to stand for 20 minbefore being quenched with ethyl acetate. The quenched reaction mixturewas filtered through celite and the solvent removed in vacuo to yield anoil. The oil was then dissolved in 5 mL of ethyl acetate and to thisethyl acetate solution was added 1 mL of HCl saturated ethyl acetate. Asolid precipitated which was collected and dried to yield9-(N,N-Dimethylaminomethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-onemonohydrochloride (Compound 24). m.p.>325° C.

EXAMPLE XV

The following compound was prepared essentially according to theprocedure of Example XIV:

(a)9-(N-Methylpiperazinylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-onemonohydrochloride (Compound 25). m.p.325°-327° C.

(b)9-(Piperidinylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-onemonohydrochloride (Compound 26). m.p.223°-226° C.

(c)9-(Hydroxymethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 27). m.p.273°-274° C.

EXAMPLE XVI ##STR30##

To 10 mL of anhydrous t-butanol was added9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(327 mg), diphenylphosphorylazide 275 mg), and triethylamine (100 mg).The resulting mixture was refluxed for 14 hours and the solvent removedin vacuo. The mixture was then triterated with 10 mL hot methanol andthe resultant solid was collected, washed with ethyl acetate, and driedto yield9-(t-Butoxycarbonylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound28), m.p.>325° C.

EXAMPLE XVII ##STR31##

To 10 mL of trifluoroacetic acid was added9-(t-Butoxycarbonylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(100 mg). After the solid dissolved, the solution was stirred for 20minutes and the TFA removed in vacuo. To the residue was added 10 mL ofwater followed by sufficient saturated aqueous sodium bicarbonate toneutralize the mixture. The mixture was subsequently cooled and thesolid collected to yield9-Amino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 29), m.p.>325° C.

EXAMPLE XVIII ##STR32##

To 50 mL of POCl₃ was added2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(600 mg) and the resultant mixture was refluxed for 48 hours. Themixture was then cooled and the POCl₃ was removed in vacuo. To theresidue was added 20 mL of water and the pH adjusted to 7 with ammoniumhydroxide. After cooling, the precipitated solid was collected to yield5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 30), m.p. 175°-176° C.

EXAMPLE XIX ##STR33##

To 5 mL of benzylamine was added5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(150 mg) and the resulting mixture heated at 100° C. for 20 min. After10 mL of water was added to the mixture, it was cooled and the solidthat precipitated was collected. The solid was recrystallized fromethanol/water to yield5-(N-Benzylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 31), m.p. 144°-145° C.

EXAMPLE XX

The following compounds were prepared according to the procedure ofExamples XVIII and XIX:

(a) 5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 32), m.p. 145°-146° C.

(b)5-Amino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 33), m.p. 255°-258° C.

(c)5-(N,N-Dimethylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 34), m.p. 158°-160° C.

(d)5-(N-Propylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound35), m.p. 180°-185° C.

(e)5-Anilino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound36), m.p. 199°-200° C.

EXAMPLE XXI ##STR34##

To 10 mL anhydrous methanol was added 100 mg of sodium, and the mixturewas stirred to ensure all the sodium had dissolved. Next,5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(200 mg) was added and the mixture refluxed for 1 h. To this mixture wasadded 2 mL of acetic acid and the solvent was then removed under reducedpressure. The resulting solid was recrystallized from ethanol andcollected to yield5-Methoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 37), m.p. 160°-161° C.

EXAMPLE XXII

The following compounds were prepared essentially according to theprocedure of Example XXI:

(a) 5-Methoxy-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 38), m.p. 147°-148° C.

(b) 5-Ethoxy-2-(2-fluorophenyl)-7,8,9,10-imidazo[1,2-c]-quinazoline(Compound 39), m.p. 186°-188° C.

(c)5-Methoxy-2-phenyl-8,9-dihydro-7H-cyclopent[g]-imidazo[1,2-c]-pyrimidine(Compound 40), m.p. 154°-156° C.

EXAMPLE XXIII ##STR35##

To a solution of 700 mg of potassium fluoride and 200 mg 18-crown-6 in10 mL of DMF was added5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(200 mg). This mixture was refluxed for 1.5 h, cooled to roomtemperature and poured into water. The aqueous solution was extractedwith ethyl acetate, the organic layer was separated and dried, and thesolvent removed in vacuo to yield5-Fluoro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 41), m.p. 154°-155° C.

EXAMPLE XXIV ##STR36##

A mixture of5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200mg), triethylamine (0.5 mL), and 100 mg of 10% palladium on carboncatalyst in 200 mL ethanol was hydrogenated at 30 psi for 4 hours. Thereaction mixture was then filtered through celite, and the solvent wasremoved in vacuo. The resulting mixture was chromatographed using 30%ethyl acetate/hexane as eluant to yield2-Phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 42),m.p. 175°-181° C.

EXAMPLE XXV

The following compound was prepared essentially according to theprocedure of Example XXIV:

(a) 2-(2'-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 43), m.p. 173°-175° C.

EXAMPLE XXVI ##STR37##

To a solution of 200 mg of potassium cyanide and 300 mg of 18-crown-6 in20 mL of acetonitrile was added5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (220mg). The mixture was refluxed for 2 hours, cooled and poured into water.The aqueous layer was extracted with dichloromethane, the organic layerseparated and dried and the solvent removed in vacuo. The resultantcrude reaction mixture was chromatographed using 15% ethylacetate/hexane as eluent to yield5-Cyano-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 44), m.p. 203°-205° C.

EXAMPLE XXVII ##STR38##

To 5.0 mL of concentrated sulfuric acid was added5-Cyano-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (80 mg).The resulting solution was then heated at 100° C. for 10 min, pouredinto cold saturated aqueous K₂ CO₃ and the solid collected and dried.The solid was extracted with dichloromethane and the solvent removed invacuo to yield crude product. The product was chromatographed using 5%methanol/methylene chloride as eluent to yield5-Carboxamido-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 45), m.p. 260°-261° C.

EXAMPLE XXVIII ##STR39##

To a solution of9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(110 mg) in 15 mL of anhydrous tetrahydrofuran was added 2 mL of 1.8Mphenylithium. The reaction was allowed to stand for 15 minutes and thenquenched with 1 mL of 10% acetic acid. The solvent was removed in vacuoand the crude reaction mixture triterated with water. The solid was thencollected and dried to yield9-(Diphenylhydroxymethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 46), m.p. 315°-318° C.

EXAMPLE XXIX ##STR40##

A mixture of2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(283 mg) and 50% sodium hydride (144 mg) in DMF (5 mL) was stirred atroom temperature for 15 min. Acetyl chloride (1 mL) was added andstirring was continued for 30 min. The reaction was diluted with ethylacetate and washed with water. After drying over magnesium sulfate, thesolvent was removed in vacuo and the residue was subjected to flashchromatography on silica gel with 30% ethyl acetate in hexane as theeluent to afford6-Acetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one(Compound 47) and5-Acetoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline(Compound 48) as white solids.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR41## andpharmaceutically acceptable non-toxic salts thereof wherein: n is 0, 1or 2;R₁, R₂, and R₃ are hydrogen or straight chain or branched loweralkyl having 1-6 carbon atoms; W is phenyl, thienyl, or pyridyl,unsubstituted or mono or disubstituted with halogen, lower alkyl, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; Y is--R₄, --OR₄, --COR₄, --CO2R₄, --OCOR₄, --CONR₄ R₅, --(CH₂)nNR₄ R₅ wheren is 0, 1, or 2 and R₄ and R₅ are the same or different and representhydrogen, phenyl, straight or branched chain lower alkyl having 1-6carbon atoms, phenylalkyl wherein the alkyl portion is straight orbranched chain lower alkyl having 1-6 carbon atoms, and NR₄ R₅ may alsorepresent N-alkyl piperazinyl, morpholinyl, piperidinyl or pyrrolidinyl,or NR₄ CO₂ R₆ where R₄ is hydrogen, phenyl straight or branched chainlower alkyl having 1-6 carbon atoms, phenylalkyl wherein the alkylportion is straight or branched chain lower alkyl having 1-6 carbonatoms and R₆ is straight or branched chain lower alkyl having 1 to 6carbon atoms and R₆ is straight or branched chain lower alkyl having 1to 6 carbon atoms or phenyl, or --C(OH)R₇ R₈ where R₇ and R₈ are thesame or different and represent hydrogen, branched or straight chainlower alkyl having 1-6 carbon atoms, phenyl or phenylalkyl wherein thealkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and X is --N═C--R₉ or --NR₁₀ --C═T, with the proviso thatwhen X is --NR₁₀ 13 C═T, T is oxygen or sulphur and R₁₀ is hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms or COR₁₁where R₁₁ is hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, straight or branched chain lower alkoxy having 1-6 carbonatoms, amino, alkylamino or dialkylamino where each alkyl is a straightor branched chain lower alkyl having 1-6 carbon atoms, and when X is--N═C--R₉, R₉ is hydrogen, halogen, cyano, phenoxy, straight or branchedchain lower alkoxy having 1-6 carbon atoms, amino, phenylamino,alkylamino, dialkylamino or arylalkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, OCOR₁₁ where R₁₁is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, straight or branched chain lower alkoxy having 1-6 carbon atoms,amino, alkylamino, dialkyl amino, arylamino, or arylalkylamino whereeach alkyl is a straight or branched chain lower alkyl having 1-6 carbonatoms, or CONHR₁₂ where R₁₂ is hydrogen or branched or straight chainlower alkyl having 1-6 carbon atoms.
 2. A compound according to claim 1of the formula: ##STR42## and the pharmaceutically acceptable non-toxicsalts thereof wherein Y is hydrogen, lower alkyl having 1-6 carbonatoms, alkanoyl having 1-6 carbon atoms, phenylalkyl wherein the alkylportion has 1-3 carbon atoms, carboalkoxy having 1-6 carbon atoms,--(CH₂)_(n) NR₄ R₅ OR --CONR₄ R₅ with n is 0 or 1 and R₄ and R₅ are thesame or differnt and represent hydrogen, phenyl, straight or branchedchain lower alkyl having 1-3 carbon atoms, phenylalkyl straight orbranched chain lower alkyl having 1-3 atoms, and NR₄,R₅ may alsorepresent N-alkyl piperazinyl, morpholinyl, peperidinyl or pyrrolidinyl,or NR₄ CO₂ R₆ where R₄ is hydrogen or methyl and R₆ is straight orbranched chain lower alkyl having 1 to 6 carbon atoms or phenyl, or--C(OH)R₇ R₈ where R₇ and R₈ are the same or different and representhydrogen, branched or straight chain lower alkyl having 1-6 carbonatoms, phenylalkyl straight or branched chain lower alkyl having 1-6carbon atoms;W is phenyl, unsubstituted or mono or disubstituted withhalogen, lower alkyl, or straight or branched chain lower alkoxy having1-6 carbon atoms; and R₉ is hydrogen, halogen, phenoxy, alkoxy having1-6 carbon atoms or OCOR₁₁ where R₁₁ is hydrogen, straight or branchedchain lower alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbonatoms, amino or dialkyl amino having 1-6 carbon atoms.
 3. A compoundaccording to claim 1 of the formula: ##STR43## and the pharmaceuticallyacceptable non-toxic salts thereof wherein Y is hydrogen, lower alkylhaving 1-6 carbon atoms, alkanoyl having 1-6 carbon atoms, phenylalkylhaving 1-3 carbon atoms, carboalkoxy having 1-6 carbon atoms,--(CH₂)_(n) NR₄ R₅ or --CONR₄ R₅ with n is 0 or 1 and R₄ and R₅ are thesame or differnt and represent hydrogen, phenyl, straight or branchedchain lower alkyl having 1-3 carbon atoms, phenylalkyl wherein the alkylportion is straight or branched chain lower alkyl having 1-3 carbonatoms, and NR₄,R₅ may also represent piperazinyl, morpholinyl,piperidinyl or pyrrolidinyl, or NR₄ CO₂ R₆ where R₄ is hydrogen ormethyl and R₆ is straight or branched chain lower alkyl having 1 to 6carbon atoms or phenyl, or --C(OH)R₇ R₈ where R₇ and R₈ are the same ordifferent and represent hydrogen, branched or straight chain lower alkylhaving 1-6 carbon atoms, phenyl or phenylalkyl wherein the alkyl portionis straight or branched chain lower alkyl having 1-6 carbon atoms;W isphenyl, unsubstituted or mono or disubstituted with halogen, loweralkyl, or straight or branched chain lower alkoxy having 1-6 carbonatoms; and T is oxygen or sulfur.
 4. A compound according to claim 1 ofthe formula: ##STR44## and the pharmaceutically acceptable non-toxicsalts thereof wherein Y is hydrogen, lower alkyl having 1-6 carbonatoms, alkanoyl having 1-6 carbon atoms, phenylalkyl having 1-3 carbonatoms, carboalkoxy having 1-6 carbon atoms, --(CH₂)_(n) NR₄ R₅ or--CONR₄ R₅ with n is 0 or 1 and R₄ and R₅ are the same or differnt andrepresent hydrogen, phenyl, straight or branched chain lower alkylhaving 1-3 carbon atoms, phenylalkyl straight or branched chain loweralkyl having 1-3 carbon atoms, and NR₄,R₅ may also representpiperazinyl, morpholinyl, piperidinyl or pyrrolidinyl, or NR₄ CO₂ R₆where R₄ is hydrogen or methyl and R₆ is straight or branched chainlower alkyl having 1 to 6 carbon atoms or phenyl, or --C(OH)R₇ R₈ whereR₇ and R₈ are the same or different and represent hydrogen, branched orstraight chain lower alkyl having 1-6 carbon atoms, phenyl orphenylalkyl wherein the alkyl portion is straight or branched chainlower alkyl having 1-6 carbon atoms; andW is phenyl, unsubstituted ormono or disubstituted with halogen, lower alkyl, or straight or branchedchain lower alkoxy having 1-6 carbon atoms.
 5. A compound to claim 1,wherein X is ##STR45## T is oxygen and n is
 1. 6. A compound accordingto claim 2, wherein W is (2 or 3)-fluorophenyl and R₁, R₂ and R₃ arehydrogen.
 7. A compound according to claim 3, wherein Y is CO₂ Et.
 8. Acompound according to claim 3, wherein Y is hydrogen.
 9. A compoundaccording to claim 3, wherein Y is CON(CH₃)₂.
 10. A compound accordingto claim 3, wherein Y is N-methyl piperizinecarbonyl.
 11. A compoundaccording to claim 3, wherein Y is N-benzylcarbamyl.
 12. A compoundaccording to claim 3, wherein Y is NHCO₂ C(CH₃)₃.
 13. A compoundaccording to claim 3, wherein Y is NH₂.
 14. A compound according toclaim 1, wherein X is ##STR46##
 15. A compound according to claim 11,wherein W is (2 or 3)-fluorophenyl.
 16. A compound according to claim12, wherein R₉ chlorine.
 17. A compound according to claim 12, whereinR₉ is benzylamino.
 18. A compound according to claim 12, wherein R₉ isphenyl amino.
 19. A compound according to claim 12, wherein R₉ isethoxy.
 20. A compound according to claim 12, wherein R₉ is CONH₂.
 21. Acompound according to claim 1 which is9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.22. A compound according to claim 1 which is2-(4-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one23. A compound according to claim 1 which is2-(2-Methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.24. A compound according to claim 1 which is2-(2-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.25. A compound to claim 1 which is2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.26. A compound according to claim 1 which is2-(4-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.27. A compound according to claim 1 which is2-(3-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.28. A compound according to claim 1 which is2(phenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.
 29. Acompound according to claim 1 which is2-(3-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.30. A compound according to claim 1 which is9-Carboethoxy-2-(3-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.31. A compound to claim 1 which is2-(4-Methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.32. A compound according to claim 1 which is2-Phenyl-8,9-dihydro-7H-cyclopent[g]-imidazo[1,2-c]-pyrimidin-5(6H)-one.33. aacompound according to claim 1 which is2-Phenyl-8,9,10,11-tetrahydro-7H-cyclohept[g]-imidazo[1,2-c]pyrimidin-5(6H)-one.34. A compound according to claim 1 which is9-Carboisopropoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.35. A compound according to claim 1 which is9-Carboisopropoxy-2-(3-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.36. A compound according to claim 1 which is9-Carbobutoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.37. A compound according to claim 1 which is9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.38. A compound according to claim 1 which is9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.39. A compound according to claim 1 which is9-(N-Methylpiperazinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.40. A compound according to claim 1 which is9-(N-Benzylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.41. A compound according to claim 1 which is9-(Piperidinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.42. A compound according to claim 1 which is9-(Pyrrolidinecarbonyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.43. A compound according to claim 1 which is9-(Morpholinecarbonyl)-2-(2-flurophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.44. A compound to claim 1 which is9-(N,N-Dimethylaminomethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-onemonohydrochloride.
 45. A compound according to claim 1 which is9-(N-Methylpiperazinylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-onemonohydrochloride.
 46. A compound according to claim 1 which is9-(Piperidinylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-onemonohydrochloride.
 47. A compound according to claim 1 which is9-(Hydroxymethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.48. A compound according to claim 1 which is9-(t-Butoxycarbonylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.49. A compound according to claim 1 which is9-Amino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.50. A compound according to claim 1 which is5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.51. A compound according to claim 1 which is5-(N-Benzylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.52. A compound according to claim 1 which is5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.
 53. Acompound according to claim 1 which is5-Amino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.54. A compound according to claim 1 which is5-(N,N-Dimethylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.55. A compound according to claim 1 which is5-(N-Propylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.56. A compound according to claim 1 which is5-Anilino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.57. A compound according to claim 1 is5-Methoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.58. A compound according to claim 1 which is5Methoxy-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.
 59. Acompound according to claim 1 which is5-Ethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.60. A compound according to claim 1 which is5-Methoxy-2-phenyl-8,9-dihydro-7H-cyclopent[g]-imidazo[1,2-c]-pyrimidine.61. A compound according to claim 1 which is5-Fluoro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.62. A compound according to claim 1 which is2-Phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.
 63. A compoundaccording to claim 1 which is2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.
 64. Acompound according to claim 1 which is5-Carboxamido-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.
 65. A compound according to claim 1 which is9-(Diphenylhydroxymethyl)-2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.66. A compound according to claim 1 which is6-Acetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one.67. A compound according to claim 1 which is5-Acetoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline.